The present invention is directed to aryl and heterocyclyl substituted pyrimidine derivatives and their pharmaceutically acceptable salts, which inhibit the enzyme, factor Xa, thereby being useful as anti-coagulants. It also relates to pharmaceutical compositions containing the derivatives or their pharmaceutically acceptable salts, and methods of their use.
Factor Xa is a member of the trypsin-like serine protease class of enzymes. A one-to-one binding of factors Xa and Va with calcium ions and phospholipid forms the prothrombinase complex which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin which polymerizes to form insoluble fibrin.
In the coagulation cascade, the prothrombinase complex is the convergent point of the intrinsic (surface activated) and extrinsic (vessel injury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363; and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulation cascade has been refined further with the discovery of the mode of action of tissue factor pathway inhibitor (TFPI) (Seminars in Hematology (1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serine protease inhibitor with three Kunitz-type domains which competes with factor Va for free factor Xa. Once formed, the binary complex of factor Xa and TFPI becomes a potent inhibitor of the factor VIIa and tissue factor complex.
Factor Xa can be activated by two distinct complexes, by tissue factor-VIIa complex on the xe2x80x9cXa burstxe2x80x9d pathway and by the factor IXa-VIIIa complex (TENase) of the xe2x80x9csustained Xaxe2x80x9d pathway in the coagulation cascade. After vessel injury, the xe2x80x9cXa burstxe2x80x9d pathway is activated via tissue factor (TF). Up regulation of the coagulation cascade occurs via increased factor Xa production via the xe2x80x9csustained Xaxe2x80x9d pathway. Down regulation of the coagulation cascade occurs with the formation of the factor Xa-TFPI complex, which not only removes factor Xa but also inhibits further factor formation via the xe2x80x9cXa burstxe2x80x9d pathway. Therefore, the coagulation cascade is naturally regulated by factor Xa.
The primary advantage of inhibiting factor Xa over thrombin in order to prevent coagulation is the focal role of factor Xa versus the multiple functions of thrombin. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, factor VIII to VIIIa, factor V to Va, and factor XI to XIa, but also activates platelets, is a monocyte chemotactic factor, and mitogen for lymphocytes and smooth muscle cells. Thrombin activates protein C, the in vivo anti-coagulant inacfivator of factors Va and VIIIa, when bound to thrombomodulin. In circulation, thrombin is rapidly inactivated by antithrombin III (ATIII) and heparin cofactor II (HCII) in a reaction which is catalyzed by heparin or other proteoglycan-associated glycosaminoglycans, whereas thrombin in tissues is inactivated by the protease, nexin. Thrombin carries out its multiple cellular activation functions through a unique xe2x80x9ctethered ligandxe2x80x9d thrombin receptor (Cell (1991), Vol. 64, p. 1057), which requires the same anionic binding site and active site used in fibrinogen binding and cleavage and by thrombomodulin binding and protein C activation. Thus, a diverse group of in vivo molecular targets compete to bind thrombin and the subsequent proteolytic events will have very different physiological consequences depending upon which cell type and which receptor, modulator, substrate or inhibitor binds thrombin.
Published data with the proteins antistasin and tick anti-coagulant peptide (TAP) demonstrate that factor Xa inhibitors are efficacious anti-coagulants (Thrombosis and Haemostasis (1992), Vol. 67, pp. 371-376; and Science (1990), Vol. 248, pp. 593-596).
The active site of factor Xa can be blocked by either a mechanism-based or a tight binding inhibitor (a tight binding inhibitor differs from a mechanism-based inhibitor by the lack of a covalent link between the enzyme and the inhibitor). Two types of mechanism-based inhibitors are known, reversible and irreversible, which are distinguished by ease of hydrolysis of the enzyme-inhibitor link (Thrombosis Res. (1992), Vol. 67, pp. 221-231; and Trends Pharmacol. Sci. (1987), Vol. 8, pp. 303-307). A series of guanidino compounds are examples of tight-binding inhibitors (Thrombosis Res. (1980), Vol. 19, pp. 339-349). Arylsulfonyl-arginine-piperidine-carboxylic acid derivatives have also been shown to be tight-binding inhibitors of thrombin (Biochem. (1984), Vol. 23, pp. 85-90), as well as a series of arylamidine-containing compounds, including 3-amidinophenylaryl derivatives (Thrombosis Res. (1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones (Thrombosis Res. (1980), Vol. 17, pp. 545-548). However, these compounds demonstrate poor selectivity for factor Xa.
European Published Patent Application 0 540 051 (Nagahara et al.) describes aromatic amidine derivatives. These derivatives are stated to be capable of showing a strong anticoagulant effect through reversible inhibition of factor Xa.
The synthesis of xcex1,xcex1xe2x80x2-bis(amidinobenzylidene)cycloalkanones and xcex1,xcex1xe2x80x2-bis(amidinobenzyl)cycloalkanones is described in Pharmazie (1977), Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as being serine protease inhibitors.
U.S. Pat. No. 5,451,700 (Morrissey et al.) describes amidino compounds. These compounds are stated to be useful as selective LTB4 receptor antagonists.
U.S. Pat. No. 5,612,363 (Mohan et al.) describes N,N-di(aryl)cyclic urea derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.
U.S. Pat. No. 5,633,381 (Dallas et al.) describes (Z,Z), (Z,E) and (E,Z) isomers of substituted bis(phenylmethylene)cycloketones. These compounds are disclosed as being factor Xa inhibitors, thereby being useful as anticoagulants.
PCT Published Patent Application WO/96/28427 (Buckman et al.) describes benzamidine derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.
PCT Published Patent Application WO/97/21437 (Arnaiz et al.) describes naphthyl-substituted benzimidazole derivatives. These compounds are disclosed as being factor Xa inhibitors, thereby being useful as anticoagulants.
PCT Published Patent Application WO/97/29067 (Kochanny et al.) describes benzamidine derivatives that are substituted by amino acid and hydroxy acid derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.
The above references, published patent applications and U.S. patents are herein incorporated in full by reference.
This invention is directed to compounds or their pharmaceutically acceptable salts which inhibit human factor Xa and are therefore useful as pharmacological agents for the treatment of disease-states characterized by thrombotic activity.
Accordingly, in one aspect, this invention provides compounds selected from the group consisting of the following formulae: 
wherein:
Z1 is xe2x80x94Oxe2x80x94, xe2x80x94N(R7)xe2x80x94, xe2x80x94CH2Oxe2x80x94 or xe2x80x94S(O)nxe2x80x94 (where n is 0 to 2);
Z2 is xe2x80x94Oxe2x80x94, xe2x80x94N(R7)xe2x80x94, xe2x80x94OCH2xe2x80x94 or xe2x80x94S(O)nxe2x80x94 (where n is 0 to 2);
R1 and R4 are each independently hydrogen, halo, alkyl, nitro, xe2x80x94OR7, xe2x80x94C(O)OR7, xe2x80x94C(O)N(R7)R8, xe2x80x94N(R7)R8, xe2x80x94N(R7)C(O)R7, or xe2x80x94N(H)S(O)2R9;
R2 is xe2x80x94C(NH)NH2, xe2x80x94C(NH)N(H)OR7, xe2x80x94C(NH)N(H)C(O)OR9, xe2x80x94C(NH)N(H)C(O)R7, xe2x80x94C(NH)N(H)S(O)2R9, or xe2x80x94C(NH)N(H)C(O)N(H)R7;
R3 is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, xe2x80x94OR7, xe2x80x94C(NH)NH2, xe2x80x94C(NH)N(H)OR7, xe2x80x94C(O)N(R7)R8, xe2x80x94R10xe2x80x94C(O)N(R7)R8, xe2x80x94CH(OH)C(O)N(R7)R8, xe2x80x94N(R7)R8, xe2x80x94R10xe2x80x94N(R7)R8, xe2x80x94C(O)OR7, xe2x80x94R10xe2x80x94C(O)OR7, xe2x80x94N(R7)C(O)R7, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);
each R5 are independently hydrogen, halo, alkyl, haloalkyl, nitro, aralkoxy, xe2x80x94OR9, xe2x80x94R10xe2x80x94OR9, xe2x80x94N(R7)R8, xe2x80x94C(O)OR7, xe2x80x94R10xe2x80x94C(O)OR7, xe2x80x94C(O)N(R7)R8, xe2x80x94R10xe2x80x94C(O)N(R7)R8, xe2x80x94C(O)N(R7)CH2C(O)N(R7)R8, xe2x80x94N(R7)C(O)N(R7)R8, xe2x80x94N(R7)C(O)R8, xe2x80x94N(O)S(O)2R9, or xe2x80x94N(R7)C(O)N(R7)xe2x80x94CH2C(O)N(R7)R8;
each R6 is aryl (optionally substituted by halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), aralkyl (wherein the aryl is optionally substituted by halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), heterocyclyl (optionally substituted by halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or heterocyclylalkyl (wherein the heterocyclyl is optionally substituted by halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);
each R7 and R8 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (wherein the aryl is optionally substituted by halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);
each R9 is alkyl, aryl (optionally substituted by halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (wherein the aryl is optionally substituted by halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), and
each R10 is independently an alkylene or alkylidene chain;
as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof.
In another aspect, this invention provides compositions useful in treating a human having a disease-state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound of the invention as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another aspect, this invention provides a method of treating a human having a disease-state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above.
In another aspect, this invention provides a method of treating a human having a disease-state alleviated by the inhibition of factor Xa, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above.
In another aspect, this invention provides a method of inhibiting human factor Xa in vitro by the administration of a compound of the invention.
As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:
xe2x80x9cAlkylxe2x80x9d refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.
xe2x80x9cAlkoxyxe2x80x9d refers to a radical of the formula xe2x80x94ORa where Ra is an alkyl radical as defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (t-butoxy), and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)ORa where Ra is an alkyl radical as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 1-methylethoxycarbonyl (iso-propoxycarbonyl), n-butoxycarbonyl, n-pentoxycarbonyl, 1,1-dimethylethoxycarbonyl (t-butoxycarbonyl), and the like.
xe2x80x9cAlkanolxe2x80x9d refers to a compound of the formula Raxe2x80x94OH where Ra is an alkyl radical as defined above, e.g., methanol, ethanol, n-propanol, etc.
xe2x80x9cAlkylene chainxe2x80x9d refers to straight or branched chain divalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to six carbon atoms, e.g., methylene, ethylene, propylene, n-butylene and the like.
xe2x80x9cAlkylidene chainxe2x80x9d refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms, wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule, e.g., ethylidene, propylidene, n-butylidene, and the like.
xe2x80x9cArylxe2x80x9d refers to a phenyl or naphthyl radical.
xe2x80x9cAralkylxe2x80x9d refers to a radical of the formula xe2x80x94RaRb where Ra is an alkyl radical as defined above, substituted by Rb, an aryl radical, as defined above, e.g., benzyl.
xe2x80x9cAralkoxyxe2x80x9d refers to a radical of the formula xe2x80x94ORc where Rc is an aralkyl radical as defined above, e.g., benzyloxy, and the like.
xe2x80x9cAmidinoxe2x80x9d refers to the radical xe2x80x94C(NH)NH2.
xe2x80x9cAminocarbonylxe2x80x9d refers to the radical xe2x80x94C(O)NH2.
xe2x80x9cDialkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94N(Ra)Ra where each Ra is independently an alkyl radical as defined above, e.g., dimethylamino, methylethylamino, diethylamino, dipropylamino, ethylpropylamino, and the like.
xe2x80x9cDialkylaminocarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)N(Ra)Ra where each Ra is independently an alkyl radical as defined above, e.g., dimethylaminocarbonyl, methylethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl, and the like.
xe2x80x9cHaloxe2x80x9d refers to bromo, chloro, iodo or fluoro.
xe2x80x9cHaloalkylxe2x80x9d refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
xe2x80x9cHeterocyclylxe2x80x9d refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclyl radical is not attached to pyrimidinyl moiety of the compounds of formula (I), (II) and (III) through a hetero atom. In addition, for purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems, and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom in the heterocyclyl radical may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated or aromatic. Examples of such heterocyclyl radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl and oxadiazolyl.
xe2x80x9cHeterocyclylalkylxe2x80x9d refers to a radical of the formula xe2x80x94Raxe2x80x94Rd where Ra is an alkyl radical as defined above and Rd is a heterocyclyl radical as defined above, for example, (4-methylpiperazin-1-yl)methyl, (morpholin-4-yl)methyl, 2-(oxazolin-2-yl)ethyl, and the like.
xe2x80x9c(1,2)-Imidazolylxe2x80x9d refers to an imidazolyl radical attached at either the 1- or 2-position.
xe2x80x9c(1,2)-Imidazolinylxe2x80x9d refers to a 4,5-dihydroimidazolyl radical attached at either the 1- or the 2-position.
xe2x80x9cMonoalkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94NHRa where Ra is an alkyl radical as defined above, e.g., methylamino, ethylamino, propylamino, and the like.
xe2x80x9cMonoalkylaminocarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)NHRa where Ra is an alkyl radical as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like.
xe2x80x9c(1,2)-Tetrahydropyrimidinylxe2x80x9d refers to a tetrahydropyrimidinyl radical attached at either the 1- or 2-position.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, xe2x80x9coptionally substituted arylxe2x80x9d means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d includes both acid and base addition salts.
xe2x80x9cPharmaceutically acceptable acid addition saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
xe2x80x9cPharmaceutically acceptable base addition saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
xe2x80x9cTherapeutically effective amountxe2x80x9d refers to that amount of a compound of the invention which, when administered to a human in need thereof, is sufficient to effect treatment, as defined below, for disease-states characterized by thrombotic activity. The amount of a compound of the invention which constitutes a xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease-state and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein covers the treatment of a disease-state in a human, which disease-state is characterized by thrombotic activity, and includes:
(i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it;
(ii) inhibiting the disease-state, i.e., arresting its development; or
(iii) relieving the disease-state, i.e., causing regression of the disease-state.
The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.
The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure. The compounds of the invention and their pharmaceutically acceptable salts may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.
The nomenclature used herein is a modified form of the I.U.P.A.C. system wherein the compounds of the invention are named as pyrimidinyl derivatives of benzamidine. For example, a compound of the invention selected from formula (I): 
where Z1 and Z2 are both xe2x80x94Oxe2x80x94, R1 is hydroxy, R2 is amidino, R3 is dimethylaminocarbonyl, R4 is hydrogen, R5 is hydrogen, and R6 is 4-methylphenyl is named herein as 4-hydroxy-3-[[6-(3-(dimethylaminocarbonyl)phenoxy)-2-(4-methylphenyl)pyrimidin-4-yl]oxy]benzamidine.
For purposes of this invention, parenthesis are used to denote substituents of a main atom of the substituent. For example, xe2x80x94C(NH)N(H)C(O)OR9 refers to the substituent of the formula: 
A. Utility
The compounds of the invention are inhibitors of the serine protease, factor Xa, and are therefore useful in disease-states characterized by thrombotic activity based on factor Xa""s role in the coagulation cascade (see Background of the Invention above). A primary indication for the compounds is prophylaxis for long term risk following myocardial infarction. Additional indications are prophylaxis of deep vein thrombosis (DVT) following orthopedic surgery or prophylaxis of selected patients following a transient ischemic attack. The compounds of the invention may also be useful for indications in which coumadin is currently used, such as for DVT or other types of surgical intervention such as coronary artery bypass graft and percutaneous transluminal coronary angioplasty. The compounds are also useful for the treatment of thrombotic complications associated with acute promyelocytic leukemia, diabetes, multiple myelomas, disseminated intravascular coagulation associated with septic shock, purpura fulminanas associated infection, adult respiratory distress syndrome, unstable angina, and thrombotic complications associated with aortic valve or vascular prosthesis. The compounds are also useful for prophylaxis for thrombotic diseases, in particular in patients who have a high risk of developing such disease.
In addition, the compounds of the invention are useful as in vitro and in vivo diagnostic reagents for selectively inhibiting factor Xa without inhibiting other components of the coagulation cascade.
B. Testing
The primary bioassays used to demonstrate the inhibitory effect of the compounds of the invention on factor Xa are simple chromogenic assays involving only serine protease, the compound of the invention to be tested, substrate and buffer (see, e.g., Thrombosis Res. (1979), Vol. 16, pp. 245-254). For example, four tissue human serine proteases can be used in the primary bioassay, free factor Xa, prothrombinase, thrombin (IIa) and tissue plasminogen activator (tPA). The assay for tPA has been successfully used before to demonstrate undesired side effects in the inhibition of the fibrinolytic process (see, e.g., J. Med. Chem. (1993), Vol. 36, pp. 314-319).
Another bioassay useful in demonstrating the utility of the compounds of the invention in inhibiting factor Xa demonstrates the potency of the compounds against free factor Xa in citrated plasma. For example, the anticoagulant efficacy of the compounds of the invention will be tested using either the prothrombin time (PT), or activated partial thromboplastin time (aPTT) while selectivity of the compounds is checked with the thrombin clotting time (TCT) assay. Correlation of the Ki in the primary enzyme assay with the Ki for free factor Xa in citrated plasma will screen against compounds which interact with or are inactivated by other plasma components. Correlation of the Ki with the extension of the PT is a necessary in vitro demonstration that potency in the free factor Xa inhibition assay translates into potency in a clinical coagulation assay. In addition, extension of the PT in citrated plasma can be used to measure duration of action in subsequent pharmacodynamic studies.
For further information on assays to demonstrate the activity of the compounds of the invention, see R. Lottenberg et al., Methods in Enzymology (1981), Vol. 80, pp. 341-361, and H. Ohno et al., Thrombosis Research (1 980), Vol. 19, pp. 579-588.
C. General Administration
Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally, topically, transdermally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. Preferably, the composition will be about 5% to 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
The preferred route of administration is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of severity of the disease-state to be treated. For such oral administration, a pharmaceutically acceptable composition containing a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharine, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
Preferably such compositions will take the form of capsule, caplet or tablet and therefore will also contain a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as croscarmellose sodium or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.
The compounds of the invention, or their pharmaceutically acceptable salts, may also be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier that slowly dissolves within the body, e.g., polyoxyethylene glycols and polyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., a compound(s) of the invention (about 0.5% to about 20%), or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington""s Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state alleviated by the inhibition of factor Xa in accordance with the teachings of this invention.
The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease-states; and the host undergoing therapy. Generally, a therapeutically effective daily dose is from about 0.14 mg to about 14.3 mg/kg of body weight per day of a compound of the invention, or a pharmaceutically acceptable salt thereof; preferably, from about 0.7 mg to about 10 mg/kg of body weight per day; and most preferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day. For example, for administration to a 70 kg person, the dosage range would be from about 10 mg to about 1.0 gram per day of a compound of the invention, or a pharmaceutically acceptable salt thereof, preferably from about 50 mg to about 700 mg per day, and most preferably from about 100 mg to about 500 mg per day.
Of the compounds of the invention as set forth above in the Summary of the Invention, a preferred group of compounds are those compounds wherein Z1 is xe2x80x94Oxe2x80x94, xe2x80x94CH2Oxe2x80x94 or xe2x80x94S(O)nxe2x80x94 (where n is 0 to 2); Z2 is xe2x80x94Oxe2x80x94, xe2x80x94OCH2xe2x80x94 or xe2x80x94S(O)nxe2x80x94 (where n is 0 to 2); R1 and R4 are each independently halo, alkyl or xe2x80x94OR7; R2 is xe2x80x94C(NH)NH2, xe2x80x94C(NH)N(H)S(O)2R9, or xe2x80x94C(NH)N(H)C(O)N(H)R7; R3 is ureido, guanidino, xe2x80x94N(R7)R8, xe2x80x94N(R7)C(O)R7, (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl); each R5 are independently hydrogen, halo, alkyl or haloalkyl; each R6 is aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), aralkyl (wherein the aryl is optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), heterocyclyl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or heterocyclylalkyl (wherein the heterocyclyl is optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); each R7 and R8 is independently hydrogen, alkyl, aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (wherein the aryl is optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); and each R9 is alkyl, aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (wherein the aryl is optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl).
Of this group of compounds, a preferred subgroup of compounds are those compounds wherein Z1 is xe2x80x94Oxe2x80x94; Z2 is xe2x80x94Oxe2x80x94; R1 is hydrogen or xe2x80x94OR7; R2 is xe2x80x94C(NH)NH2; R3 is (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl); R4 is hydrogen; each R5 is hydrogen or halo; and each R6 is aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), aralkyl (wherein the aryl is optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), heterocyclyl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or heterocyclylalkyl (wherein the heterocyclyl is optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); and each R7 is independently hydrogen or alkyl.
Of this subgroup of compounds, a preferred class of compounds are those compounds wherein Z1 is xe2x80x94Oxe2x80x94; Z2 is xe2x80x94Oxe2x80x94; R1 is xe2x80x94OR7; R2 is xe2x80x94C(NH)NH2; R3 is (1,2)-imidazolyl (optionally substituted by methyl) or (1,2)-imidazolinyl (optionally substituted by methyl); R4 is hydrogen; R5 is hydrogen; and R6 is aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); and R7 is hydrogen or alkyl.
Of this class of compounds, a preferred subclass of compounds are those compounds wherein the compound is selected from the formula (I): 
Of this subclass of compounds, preferred compounds are those compounds wherein R1 is hydroxy; R3 is 1-methylimidazolin-2-yl; and R6 is aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl).
Of these preferred compounds, a more preferred compound is 4-hydroxy-3-[[6-(3-(1-methylimidazolin-2-yl)phenoxy)-2-(phenyl)pyrimidin-4-yl]oxy]benzamidine.
Of the class of compounds described above, another preferred subclass of compounds are those compounds selected from formula (II): 
Of this subclass of compounds, preferred compounds are those compounds wherein R1 is hydroxy; R3 is 1-methylimidazolin-2-yl; and R6 is aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl).
Of these preferred compounds, a more preferred compound is 4-hydroxy-3-[[4-(3-(1-methylimidazolin-2-yl)phenoxy)-6-(phenyl)pyrimidin-2-yl]oxy]benzamidine.
Of the class of compounds described above, another preferred subclass of compounds are those compounds selected from formula (III): 
Of this subclass of compounds, preferred compounds are those compounds wherein R1 is hydroxy; R3 is 1-methylimidazolin-2-yl; and R6 is aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl).
Of these preferred compounds, a more preferred compound is 4-hydroxy-3-[[2-(3-(1-methylimidazolin-2-yl)phenoxy)-6-(phenyl)pyrimidin-4-yl]oxy]benzamidine.
As a matter of convenience, the following description of the preparation of the compounds of the invention is directed to the preparation of compounds of the invention where Z1 and Z2 are both xe2x80x94Oxe2x80x94, and R2 is xe2x80x94C(NH)NH2. It is understood, however, that similar synthetic processes may be used to prepare other compounds of formula (I), (II), and (III). It is also understood that in the following description, combinations of substituents and/or variables (e.g., R7 and R8) on the depicted formulae are permissible only if such combinations result in stable compounds.
Compounds of formula (C) are intermediates in the preparation of compounds of the invention and are prepared as described below in Reaction Scheme 1 where R5 and R6 are as described above in the Summary of the Invention and R11 is alkyl or aralkyl: 
Compounds of formula (A) and formula (B) are commercially available, or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (C) are prepared by first treating an alkanol, preferably ethanol, to a molar excess amount of an alkaline metal, preferably sodium. After the metal is completely dissolved, a compound of formula (A) and a compound of formula (B) are added in equimolar amounts to the solution at ambient temperature. The resulting reaction mixture is heated to reflux for about 4 to about 6 hours, preferably for about 4 hours. The solvent is removed and a strong acid, preferably hydrochloric acid, is added to the reaction mixture to afford a precipitate, which is collected and dried to afford the compound of formula (C).
Compounds of formula (G) are intermediates in the preparation of compounds of the invention and are prepared as illustrated below in Reaction Scheme 2 wherein R5 and R6 are as described above in the Summary of the Invention and R11 is alkyl or aralkyl: 
Compounds of formula (D) and formula (E) are commercially available, or may be prepared according to methods known to those of ordinary skill in the art.
In general, compounds of formula (G) are prepared by first treating an alkanol, preferably ethanol, to a molar excess amount of an alkaline metal, preferably sodium. After the metal is completely dissolved, a compound of formula (D) and a compound of formula (E) in equimolar amounts are added to the solution. The reaction mixture is heated for about 8 to about 16 hours, preferably for about 16 hours. The solvent is removed and the residue dissolved in water. A strong acid, preferably hydrochloric acid, is added to the solution and the resulting precipitate is collected and dried to form a compound of formula (G).
Compounds of formula (H) are intermediates in the preparation of the compounds of the invention and are prepared as illustrated below in Reaction Scheme 3 wherein R5 and R6 are as described above in the Summary of the Invention: 
Compounds of formula (C) are prepared by methods described herein.
In general, compounds of formula (H) are prepared by treating a compound of formula (C) with a slight molar excess of a chlorinating agent, preferably phosphorus oxychloride, in the presence of a base, such as N,N-diethylaniline. The resulting reaction mixture is refluxed for about 2 to about 4 hours, preferably for about 3 hours, and then ice is added to the solution to afford a precipitate, which is collected and dried to afford a compound of formula (H).
In a similar manner, compounds of formula (G) may be chlorinated to form the dichloro-substituted compounds.
Compounds of formula (Ia) are compounds of the invention selected from formula (I), and are prepared as illustrated below in Reaction Scheme 4 where R1, R3, R4, R5 and R6 are as described above in the Summary of the Invention. Prior to Step 1 compounds of formula (H), formula (J) and formula (L) wherein the R1, R3, R4, R5 and R6 substituents contain additional reactive hydroxy or amino groups may be treated with the appropriate oxygen-or nitrogen-protecting group according to methods known to those skilled in the art, such as those described in Greene, T. W., Protective Groups in Organic Synthesis (1981), John Wiley and Sons, New York, N.Y. Such protected substituents will be deprotected during the reaction conditions of Step 3 to form the desired R1, R3, R4, R5 and R6 substituents. Alternatively, compounds of formula (H), formula (J) and formula (L) may already be present in an oxygen- or nitrogen-protected form and may be deprotected by methods known to those skilled in the art or, as a result of the reaction conditions of Step 3, may become deprotected to form the desired substituent. 
Compounds of formula (H) are prepared by methods disclosed herein. Compounds of formula (J) and formula (L) are commercially available or may be prepared according to methods known to those skilled in the art.
In general, the compounds of formula (Ia) are prepared by first treating a compound of formula (H) in an aprotic solvent, for example, acetonitrile, with an equimolar amount of a compound of formula (J) in the presence of a base, for example, cesium carbonate, at temperatures between about 20xc2x0 C. and 120xc2x0 C., preferably at ambient temperature, for a period of time sufficient to complete the desired reaction as monitored by thin layer chromatography (LC). The compound of formula (K) is then isolated from the reaction mixture by standard isolation techniques, such as extraction, in vacuo removal of solvent, and flash chromatography.
The compound of formula (K) in an aprotic solvent, for example, DMSO, is then treated with an equimolar amount of a compound of formula (L) in the presence of a base, for example, cesium carbonate, at temperatures between about 20xc2x0 C. and 120xc2x0 C., preferably at about 50xc2x0 C., for a period of time sufficient to complete the desired reaction, for example, for about 24 hours. The reaction mixture is cooled to ambient temperature and the compound of formula (M) is then isolated from the reaction mixture through standard isolation techniques, such as extraction, in vacuo removal of solvent, and flash chromatography.
The compound of formula (M) is dissolved in an anhydrous alkanol, preferably ethanol, and then anhydrous mineral acid, preferably HCl, is added to the solution over a period of time sufficient to saturate the acid into the solution while maintaining the reaction temperatures at about xe2x88x9278xc2x0 C. After saturation is complete, the reaction vessel is sealed and the reaction mixture is allowed to warm to ambient temperature and stirred between 12 and 24 hours, preferably for about 18 hours. The solvent is removed in vacuo and the resulting residue is dissolved in fresh anhydrous alkanol, preferably ethanol, and then treated with anhydrous ammonia (gas) at temperatures from between ambient temperature and about 100xc2x0 C. from about 1 to about 48 hours, preferably at about 60xc2x0 C. and for about 2 hours. The compound of formula (Ia) is then isolated from the reaction mixture by standard isolation techniques, for example, in vacuo removal of solvent and purification by high performance liquid chromatography (HPLC). During this last step, compounds of formula (G) where any R1, R3, R4, R5, or R6 substituent is in an oxygen- or nitrogen-protected form are deprotected to form compounds of formula (Ia) where R1, R3, R4, R5 or R6 is as defined above in the Summary of the Invention.
Alternatively, instead of treating the resulting residue above with anhydrous ammonia (gas), the resulting residue may be treated with a compound of the formula NH2OR7 to afford the corresponding compound of formula (Ia) wherein R2 is xe2x80x94C(NH)N(H)OR7.
Compounds of formula (Ia) wherein R3 is xe2x80x94C(NH)NH2 or xe2x80x94C(NH)N(H)OR7 are produced from the corresponding cyano compounds in a similar manner as that described above for compound of formula (M).
Compounds of formula (Ia) wherein R1, R3, R4, R5, R6, R7, R8 or R9 contains an alkoxycarbonyl group or a xe2x80x94C(O)OR7 group where R7 is aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl) may be prepared from the corresponding activated acid, such as an acid halide by techniques known to those of ordinary skill in the art.
Compounds of formula (Ia) wherein R1, R3, R4, R5, R6, R7, R8 or R9 contains an aminocarbonyl group, a monoalkylaminocarbonyl group, a dialkylaminocarbonyl group, a xe2x80x94C(O)N(R7)R8 group or a xe2x80x94C(O)OR7 group (where each R7 or R6 is independently alkyl, aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl) or aralkyl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl) may also be hydrolyzed under acidic conditions to prepare corresponding compounds of the invention where R1, R3, R4, R5, R6, R7, R8 or R9 contains a carboxy or a xe2x80x94C(O)OH group.
Compounds of formula (Ia) wherein R1, R3, R4, R5, R6, R7, R8 or R9 contains a carboxy group, an alkoxycarbonyl group, or a xe2x80x94C(O)OR7 group where R7 is hydrogen, alkyl, aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl) may also be amidated under standard amidation conditions to form the corresponding compounds of formula (Ia) where R1, R3, R4, R5, R6, R7, R8 or R9 contains an aminocarbonyl group, a monoalkylaminocarbonyl group, a dialkylaminocarbonyl group or a xe2x80x94C(O)N(R7)R8 group where R7 and R8 are independently hydrogen, alkyl, aryl (optionally substituted by halo, haloakyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl).
Compounds of formula (Ia) where R1, R3, R4, R5, R6, R7, R8 or R9 contains a nitro group also be reduced under standard conditions to produce the corresponding compounds of formula (Ia) where R1, R3, R4, R5, R6, R7, R8 or R9 contains an amino group, which may also be treated with the appropriate alkylating agents or acylating agents to afford the corresponding compounds of formula (Ia) where R1, R3, R4, R5, R6, R7, R8 or R9 contains a monoalkylamino group, a dialkylamino group, a xe2x80x94N(R7)R10 group or a xe2x80x94N(R7)C(O)R7 where each R7 and R10 is independently hydrogen, alkyl, or aralkyl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl).
Compounds of formula (Ia) may also be further treated with the appropriate acid halide, preferably acid chloride, or with the appropriate acid anhydride or an equivalent, to yield compounds of the invention wherein R2 is xe2x80x94C(NH)N(H)C(O)R7 where R7 is hydrogen, alkyl, aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl).
Alternatively, compounds of formula (Ia) may further be treated with a compound of formula Clxe2x80x94C(O)xe2x80x94OR9 or its functional equivalent to yield compounds of the invention where R2 is xe2x80x94C(NH)N(H)C(O)OR9 where R9 is alkyl, aryl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, haloalkyl, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl).
Alternatively, compounds of formula (Ia) may also be further treated with compounds of the formula R9xe2x80x94S(O)2-imidazole (where R9 is defined above in the Summary of the Invention) in a polar solvent, such as methylene chloride, at ambient temperature to afford compounds of the invention where R2 is xe2x80x94C(NH)N(H)S(O)2R9 where R9 is defined above in the Summary of the Invention.
Alternatively, compounds of formula (Ia) may be further treated with an appropriately Nxe2x80x94R7-substituted phenylcarbamate in a polar solvent, preferably methylene chloride, at ambient temperature, for about 6 to 24 hours, preferably for about 12 hours, to afford compounds of the invention where R2 is xe2x80x94C(NH)N(H)C(O)N(H)R7 where R7 is defined above in the Summary of the Invention.
Compounds of formula (Ia) which contain an unoxidized sulfur atom may be oxidized with the appropriate oxidizing agent to produce compounds containing oxidized sulfur (i.e., xe2x80x94S(O)nxe2x80x94 where n is 1 or 2).
In a similar manner to the reactions described above, compounds of formula (II) and (III) may be prepared.
All compounds of the invention as prepared above which exist in free base or acid form may be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid. Salts of the compounds prepared above may be converted to their free base or acid form by standard techniques.